Journal of Cerebral Blood Flow and Metabolism最新文献

Obtaining the arterial input function (AIF) is essential for quantitative regional cerebral perfusion (rCBF) measurements using [¹⁵O]H₂O PET. However, arterial blood sampling is invasive and complicates the scanning procedure. We propose a new non-invasive dual scan technique with an image derived input function (IDIF) from an additional heart scan. Six patients and two healthy subjects underwent [¹⁵O]H₂O PET imaging of 1) heart and brain during baseline, and 2) heart and brain after infusion of acetazolamide. The IDIF was extracted from the left ventricle of the heart and compared to the AIF. The rCBF was compared for six bilateral cortical regions. AIFs and IDIFs showed strong agreement. rCBF with AIF and IDIF showed strong correlation for both baseline rCBF (R² = 0.99, slope = 0.89 CI: [0.87; 0.91], p < 0.0001) and acetazolamide rCBF (R² = 0.98, slope = 0.93, CI:[0.90;0.97], p < 0.0001) but showed a positive bias of 0.047 mL/(g·min) [-0.025; +0.119] for baseline and 0.024 [-1.04, +1.53] mL/(g·min) for acetazolamide. In conclusion, the invasive arterial cannulation can be replaced by an additional scan of the heart with a minor bias of rCBF estimation. The method is applicable to all scanner systems.

Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9^-/-) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9^-/- mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO₂) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO₂. MMP-9^-/- attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice.

Delayed cerebral ischemia (DCI) following an aneurysmal subarachnoid hemorrhage (aSAH) significantly impacts mortality, morbidity, and healthcare costs. This study assessed the diagnostic accuracy of Transcranial Doppler (TCD)-derived biomarkers for predicting DCI via a systematic review and meta-analysis. Included studies had to correctly define DCI and report data on sensitivity, specificity, positive predictive value, and negative predictive value. Univariate or bivariate analyses with a random effects model were used, and risk of bias was evaluated with the Quality Assessment of Diagnostic Accuracy Studies. From 23 eligible articles (n = 2371 patients), three biomarker categories were identified: cerebral blood flow velocities (CBFV), cerebral autoregulation, and microembolic signals (MES). The highest sensitivity (0.86, 95% CI 0.71-0.94) and specificity (0.75, 95% CI 0.52-0.94) for DCI prediction were achieved with a mean CBFV of 120 cm/s combined with a Lindegaard ratio. The transient hyperemic response test showed the best performance among autoregulatory biomarkers with a sensitivity of 0.88, (95% CI 0.54-0.98) and specificity of 0.82 (95% CI 0.52-0.94). MES were less effective predictors. Combining CBFV with autoregulatory biomarkers enhanced TCD's predictive value. High heterogeneity and risk of bias were noted, indicating the need for a standardized TCD approach for improved DCI evaluation.

Blood-brain barrier (BBB) dysfunction occurs in numerous central nervous system disorders. Unfortunately, a limited understanding of the mechanisms governing barrier function hinders the identification and assessment of BBB-targeted therapies. Previously, we found that non-muscle myosin light chain kinase (nmMLCK) negatively regulates the tight junction protein claudin-5 in brain microvascular endothelial cells (BMVECs) under inflammatory conditions. Here, we used complementary animal and primary cell co-culture models to further investigate nmMLCK and claudin-5 during neuroinflammation. We found that nmMLCK-knockout mice resisted experimental autoimmune encephalomyelitis (EAE), including paralysis, demyelination, neutrophil infiltration, and BBB dysfunction. However, transiently silencing claudin-5 culminated in a fulminant disease course. In parallel, we found that neutrophil-secreted factors triggered a biphasic loss in the barrier quality of wild-type BMVEC monolayers, plus pronounced neutrophil migration during the second phase. Conversely, nmMLCK-knockout monolayers resisted barrier dysfunction and neutrophil migration. Lastly, we found an inverse relationship between claudin-5 expression in BMVECs and neutrophil migration. Overall, our findings support a pathogenic role for nmMLCK in BMVECs during EAE that includes BBB dysfunction and neutrophil infiltration, reveal that claudin-5 contributes to the immune barrier properties of BMVECs, and underscore the harmful effects of claudin-5 loss during neuroinflammation.

Neurological disorders, including brain cancer, neurodegenerative diseases and ischemic/reperfusion injury, pose a significant threat to global human health. Due to the high metabolic demands of nerve cells, mitochondrial dysfunction is a critical feature of these disorders. The mitochondrial unfolded protein response (UPR^mt) is an evolutionarily conserved mitochondrial response, which is critical for maintaining mitochondrial and energetic homeostasis under stress. Previous studies have found that UPR^mt participates in diverse physiological processes especially metabolism and immunity. Currently, increasing evidence suggest that targeted regulation of UPR^mt can also effectively delay the progression of neurological diseases and improve patients' prognosis. This review provides a comprehensive overview of UPR^mt in the context of neurological diseases, with a particular emphasis on its regulatory functions. Additionally, we summarize the mechanistic insights into UPR^mt in neurological disorders as investigated in preclinical studies, as well as its potential as a therapeutic target in the clinical management of neurological tumors. By highlighting the importance of UPR^mt in the complex processes underlying neurological disorders, this review aims to bridge current knowledge gaps and inspire novel therapeutic strategies for these conditions.

Mitochondrial transplantation is an emerging therapeutic approach for ischemia-reperfusion injury, offering the potential to restore cellular function through the engraftment of extracellular mitochondria. The successful clinical application of this strategy depends on the delivery of metabolically active mitochondria, yet the impact of circulating therapeutic agents on mitochondrial viability remains poorly understood. This study evaluates the effects of five clinically relevant agents commonly used during endovascular treatment of ischemic stroke-alteplase, cefazolin, lidocaine, phenylephrine, and heparinized saline-on extracellular mitochondria using an ex vivo model. Mitochondria were isolated from human skeletal muscle and mouse liver and exposed to these agents at clinically relevant and supra-physiological concentrations. Metabolic activity was assessed using a resazurin reduction assay as an indicator of mitochondrial viability. Even at concentrations up to 8-fold above clinical exposure, none of the agents significantly impaired mitochondrial function. These findings provide critical toxicological data demonstrating the compatibility of commonly used therapeutics with mitochondrial transplantation, supporting the development of safer and more optimized clinical protocols.

Extracellular vesicles (EVs) facilitate the transfer of biological materials between cells throughout the body. Mitochondria, membrane-bound organelles present in the cytoplasm of nearly all eukaryotic cells, are vital for energy production and cellular homeostasis. Recent studies highlight the critical role of the transport of diverse mitochondrial content, such as mitochondrial DNA (mt-DNA), mitochondrial RNA (mt-RNA), mitochondrial proteins (mt-Prots), and intact mitochondria by small EVs (<200 nm) and large EVs (>200 nm) to recipient cells, where these cargos contribute to cellular and mitochondrial homeostasis. The interplay between EVs and mitochondrial components has significant implications for health, metabolic regulation, and potential as biomarkers. Despite advancements, the mechanisms governing EV-mitochondria crosstalk and the regulatory effect of mitochondrial EVs remain poorly understood. This review explores the roles of EVs and their mitochondrial cargos in health and disease, examines potential mechanisms underlying their interactions, and emphasizes the therapeutic potential of EVs for neurological and systemic conditions associated with mitochondrial dysfunction.

Mitochondrial metabolism in neurons is necessary for energetically costly processes like synaptic transmission and plasticity. As post-mitotic cells, neurons are therefore faced with the challenge of maintaining healthy functioning mitochondria throughout lifetime. The precise mechanisms of mitochondrial maintenance in neurons, and particularly in morphologically complex dendrites and axons, are not fully understood. Evidence from several biological systems suggests the regulation of cellular metabolism by extracellular vesicles (EVs), secretory lipid-enclosed vesicles that have emerged as important mediators of cell communication. In the nervous system, neuronal and glial EVs were shown to regulate neuronal circuit development and function, at least in part via the transfer of protein and RNA cargo. Interestingly, EVs have been implicated in diseases characterized by altered metabolism, such as cancer and neurodegenerative diseases. Furthermore, nervous system EVs were shown to contain proteins related to metabolic processes, mitochondrial proteins and even intact mitochondria. Here, we present the current knowledge of the mechanisms underlying neuronal mitochondrial maintenance, and highlight recent evidence suggesting the regulation of synaptic mitochondria by neuronal and glial cell EVs. We further discuss the potential implications of EV-mediated regulation of mitochondrial maintenance and function in neuronal circuit development and synaptic plasticity.

Acute ischemic stroke (AIS) requires detailed etiology information to guide optimal management. Given the pivotal role of lipids in AIS, we conducted a comprehensive lipidomics analysis of paired thrombi and plasma from AIS patients, correlating the findings with stroke etiology. Patients were recruited across four etiologies: cardioembolism (CE), large artery atherosclerosis (LAA), active cancer (Cancer), and undetermined. Plasma and thrombi were collected before and during endovascular thrombectomy and analyzed using in-house targeted lipidomics. Among 51 patients (37 CE, 7 LAA, 4 Cancer, and 3 undetermined), we identified 37 and 70 lipid species significantly different between thrombi in CE and LAA, and CE and Cancer, respectively (FDR-corrected P < 0.05). No significant differences were observed in plasma. Notably, 21 diacylglycerols and 11 polyunsaturated triacylglycerols were depleted (2.5 to 12 folds) in LAA compared to CE, while 10 ceramides and 57 glycerophospholipids were elevated in Cancer. With 80% validation accuracy, 29 and 59 lipids distinguished LAA and Cancer from CE, respectively. A neural network model using these lipids effectively classified undetermined patients. This study emphasizes the significance of thrombus lipids in distinguishing between LAA, CE, and Cancer etiologies in AIS, enhancing our understanding of stroke pathophysiology and informing future clinical managements.

Korean red ginseng extract (KRGE) enhances astrocytic functions through hypoxia-inducible factor-1α (HIF-1α). Astrocytic Ca²⁺ influx through L-type Ca²⁺ channels (LTCCs) facilitates neurovascular communication, while the large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channel mediates K⁺ efflux for vasodilation. However, the role of LTCC subunits in KRGE-mediated BKα and HIF-1α expression in astrocytes remains unclear. This study aimed to investigate the effects of KRGE on LTCC subunits, cytosolic Ca²⁺ influx, and BKα and HIF-1α induction in human astrocytes. The levels of BKα, LTCCs, and HIF-1α were analyzed in KRGE-treated mouse brain tissue using immunohistochemistry. Human astrocytes treated with an LTCC agonist exhibited increased BKα and HIF-1α protein levels. Similarly, KRGE increased the levels of LTCC subunits α1 C and β4, cytosolic Ca²⁺ influx, BKα, and HIF-1α. Moreover, knockdown of either α1 C or β4 attenuated KRGE-induced increases in Ca²⁺ influx and HIF-1α levels. Notably, their combined knockdown synergistically reduced KRGE-induced increases in BKα levels, mitochondrial mass, ATP production, and O₂ consumption. The corpus callosum astrocytes of KRGE-treated mice exhibited increased levels of α1 C and β4, BKα, HIF-1α, and cAMP-response element binding protein (CREB). Collectively, these findings suggest that KRGE induced astrocytic BKα and HIF-1α expression via LTCC-mediated Ca²⁺ influx and subsequent CREB activation.